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Thalomid (Thalidomide) - Description and Clinical Pharmacology

 
 



DESCRIPTION

THALOMID, α-(N-phthalimido) glutarimide, is an immunomodulatory agent. The empirical formula for thalidomide is C13H10N2O4 and the gram molecular weight is 258.2. The CAS number of thalidomide is 50-35-1.

                                   Chemical Structure of Thalidomide

Thalidomide is an off-white to white, odorless, crystalline powder that is soluble at 25°C in dimethyl sulfoxide and sparingly soluble in water and ethanol. The glutarimide moiety contains a single asymmetric center and, therefore, may exist in either of two optically active forms designated S-(-) or R-(+). THALOMID is an equal mixture of the S-(-) and R-(+) forms and, therefore, has a net optical rotation of zero.

THALOMID is available in 50 mg, 100 mg, 150 mg and 200 mg capsules for oral administration. Active ingredient: thalidomide. Inactive ingredients: pregelatinized starch and magnesium stearate. The 50 mg capsule shell contains gelatin, titanium dioxide, and black ink. The 100 mg capsule shell contains black iron oxide, yellow iron oxide, titanium dioxide, gelatin, and black ink. The 150 mg capsule shell contains FD&C blue #2, black iron oxide, yellow iron oxide, titanium dioxide, gelatin, and black and white ink. The 200 mg capsule shell contains FD&C blue #2, titanium dioxide, gelatin, and white ink.

CLINICAL PHARMACOLOGY

Mechanism of Action

The mechanism of action of THALOMID is not fully understood. THALOMID possesses immunomodulatory, antiinflammatory and antiangiogenic properties. Available data from in vitro studies and clinical trials suggest that the immunologic effects of this compound can vary substantially under different conditions, but may be related to suppression of excessive tumor necrosis factor-alpha (TNF-α) production and down-modulation of selected cell surface adhesion molecules involved in leukocyte migration. For example, administration of thalidomide has been reported to decrease circulating levels of TNF-α in patients with erythema nodosum leprosum (ENL); however, it has also been shown to increase plasma TNF-α levels in HIV-seropositive patients. Other anti-inflammatory and immunomodulatory properties of thalidomide may include suppression of macrophage involvement in prostaglandin synthesis, and modulation of interleukin-10 and interleukin-12 production by peripheral blood mononuclear cells. Thalidomide treatment of multiple myeloma patients is accompanied by an increase in the number of circulating natural killer cells, and an increase in plasma levels of interleukin-2 and interferon-gamma (T cell-derived cytokines associated with cytotoxic activity).  Thalidomide was found to inhibit angiogenesis in a human umbilical artery explant model in vitro. The cellular processes of angiogenesis inhibited by thalidomide may include the proliferation of endothelial cells.

Pharmacokinetics

Absorption

Absorption of THALOMID is slow after oral administration. The maximum plasma concentrations are reached approximately 2-5 hours after administration. The absolute bioavailability of thalidomide from thalidomide capsules has not yet been characterized in human subjects due to its poor aqueous solubility. Based on the 14C-radiolabel thalidomide study in human, greater than 90% of the total radioactivity is recovered in urine suggesting good oral absorption. While the extent of absorption (as measured by area under the curve [AUC]) is proportional to dose in healthy subjects, the observed peak concentration (Cmax) increased in a less than proportional manner (see Table 5 below). This lack of Cmax dose proportionality, coupled with the observed increase in Tmax values, suggests that the poor solubility of thalidomide in aqueous media may be hindering the rate of absorption.

Table 5: Pharmacokinetic Parameter Values for THALOMID Mean (%CV)
Population/
Single Dose

AUC0-∞
µg·hr/mL

Cmax
µg/mL

Tmax
(hrs)

Half‑life
(hrs)

Healthy Subjects (n=14)
50 mg 4.9 (16%) 0.62 (52%) 2.9 (66%) 5.52 (37%)
200 mg 18.9 (17%) 1.76 (30%) 3.5 (57%) 5.53 (25%)
400 mg 36.4 (26%) 2.82 (28%) 4.3 (37%) 7.29 (36%)
Patients with Hansen’s Disease (n=6)
400 mg 46.4 (44.1%) 3.44 (52.6%) 5.7 (27%) 6.86 (17%)

Coadministration of THALOMID® (thalidomide) with a high-fat meal causes minor (<10%) changes in the observed AUC and Cmax values; however, it causes an increase in Tmax to approximately 6 hours.

Distribution

In human plasma, the geometric mean plasma protein binding was 55% and 66%, respectively, for (+)-(R)- and (-)-(S)-thalidomide. In a pharmacokinetic study of thalidomide in HIV-seropositive adult male subjects receiving thalidomide 100 mg/day, thalidomide was detectable in the semen.

Metabolism

In a 14C-radiolabel ADME study in humans, unchanged drug is the predominant circulating component. Thalidomide is not a substrate of the cytochrome P450 system.   At therapeutic concentrations, thalidomide is not an inhibitor or inducer of human cytochrome P450 enzymes in vitro.  Pharmacokinetic drug-drug interactions with substrates, inhibitors or inducers of CYP450 are not anticipated.

Elimination

The mean elimination half-life of thalidomide in plasma following single oral doses between 50 mg and 400 mg was 5.5 to 7.3 hours. Following a single 400 mg oral dose of radiolabeled thalidomide, the total mean recovery was 93.6% of the administered dose by Day 8. The majority of the radioactive dose was excreted within 48 hours following dose administration. In humans, 14C-thalidomide is primarily excreted in urine (91.9% of the radioactive dose) mainly as hydrolytic metabolites while fecal excretion is minor (<2% of the dose).  Unchanged thalidomide is not eliminated by the kidney to a notable degree (<3.5% of the dose).

Effects of Weight

There is a linear relationship between body weight and estimated thalidomide clearance.  In MM patients with body weight from 47-133 kg, thalidomide clearance ranged from approximately 6-12 L/h, representing an increase in thalidomide clearance of 0.605 L/h per 10 kg body weight increase.

Effects of Age, Gender and Race

Analysis of the data from pharmacokinetic studies in healthy volunteers and patients with Hansen’s disease ranging in age from 20 to 69 years does not reveal any age-related changes.

While a comparative trial of the effects of gender on thalidomide pharmacokinetics has not been conducted, examination of the data for thalidomide does not reveal any significant gender differences in pharmacokinetic parameter values.

Pharmacokinetic differences due to race have not been studied.

Pharmacokinetic Data in Special Populations

HIV-seropositive Subjects: There is no apparent significant difference in measured pharmacokinetic parameter values between healthy human subjects and HIV-seropositive subjects following single-dose administration of THALOMID Capsules.

Patients with Hansen’s Disease: Analysis of data from a small study in Hansen’s patients suggests that these patients, relative to healthy subjects, may have an increased bioavailability of THALOMID. The increase is reflected both in an increased area under the curve and in increased peak plasma levels. The clinical significance of this increase is unknown.

Pediatric: No pharmacokinetic data are available in subjects below the age of 18 years.

NONCLINICAL TOXICOLOGY

Carcinogenesis, Mutagenesis, Impairment of Fertility

Two-year carcinogenicity studies were conducted in male and female rats and mice. No compound-related tumorigenic effects were observed at the highest dose levels of 3,000 mg/kg/day to male and female mice (38-fold greater than the highest recommended daily human dose of 400 mg based upon body surface area [BSA]), 3,000 mg/kg/day to female rats (75-fold the maximum human dose based upon BSA), and 300 mg/kg/day to male rats (7.5-fold the maximum human dose based upon BSA).

Thalidomide was neither mutagenic nor genotoxic in the following assays: the Ames bacterial (S. typhimurium and E. coli) reverse mutation assay, a Chinese hamster ovary cell (AS52/XPRT) forward mutation assay, and an in vivo mouse micronucleus test.

Fertility studies were conducted in male and female rabbits; no compound-related effects in mating and fertility indices were observed at any oral thalidomide dose level including the highest of 100 mg/kg/day to female rabbits and 500 mg/kg/day to male rabbits (approximately 5- and 25-fold the maximum human dose, respectively, based upon BSA). Testicular pathological and histopathological effects (classified as slight) were seen in male rabbits at dose levels ≥30 mg/kg/day (approximately 1.5-fold the maximum human dose based upon BSA).

CLINICAL STUDIES

Multiple Myeloma (MM)

The efficacy and safety of THALOMID in patients with multiple myeloma were evaluated in two randomized, multi-center studies (Study 1 and Study 2).  Study 1 was an open-label study which randomized 207 symptomatic patients with newly diagnosed MM to THALOMID plus dexamethasone (N = 103) versus dexamethasone alone (N=104). The THALOMID dose was 200 mg daily and the dexamethasone dose was 40 mg orally once daily on days 1-4, 9-12, and 17-20 every 28-days. Each group was treated for four 28-day cycles.

Study 2 randomized 470 newly diagnosed patients with MM to THALOMID plus dexamethasone (N=235) versus placebo plus dexamethasone (N=235). In the THALOMID/dexamethasone arm, a starting dose of thalidomide 50 mg was escalated to 200 mg/day (cycle 2) once daily for 28 days. Patients in both treatment groups took 40 mg of dexamethasone once daily given on days 1-4, 9-12, and 17-20 (every 28 days). Beginning with Cycle 5, the dose of dexamethasone was reduced to 40 mg once daily on Days 1 to 4 of each cycle. Treatment continued as tolerated until disease progression.

Baseline demographics for both studies are presented in Table 6 and disease characteristics for the study population are summarized in Tables 7 (Study 1) and 8 (Study 2).

Table 6: Baseline Patient Demographics
Study 1 Study 2

Characteristic
THALOMID/
Dexamethasone
(N=103)
Dexamethasone
(N=104)
THALOMID/
Dexamethasone
(N=235)
Placebo/
Dexamethasone
(N=235)

1Missing information in Study 1 for 1 patient in the Dex alone group

2Missing information in Study 1 for 1 patient per arm

3Black/Hispanic [1 (0.4%)], Hispanic [2 (0.9%)], Hispanic/White [1 (0.4%)], Other [0 (0.0%)]

4Hispanic [1 (0.4%)], Asian/Pacific Islander [2 (0.9%)], Other [1 (0.4%)]

Age (years)
      Median 65 68 65 66
      Range 37 – 83 38 – 83 39 – 86 31 – 84
Gender1, N (%)
      Male 53 (51) 61 (59) 118 (50) 120 (51)
      Female 50 (49) 42 (40) 117 (50) 115 (49)
Race2, N (%)
      Caucasian 90 (87) 90 (87) 224 (95) 221 (94)
      Black 11 (11) 11 (11) 7 (3) 10 (4)
      Other 1 (1) 2 (2) 4 (2)3 4 (2)4
Table 7: Baseline Disease Characteristics (Study 1)

Disease Characteristic
THALOMID/Dexamethasone
(N=103)
Dexamethasone alone
(N=104)

1 Missing information for 1 patient in Thal + Dex arm

2 Missing information for 19 patients in Thal + Dex arm and 20 patients in Dex alone arm

3 Missing information for 17 patients in Thal + Dex arm and 30 patients in Dex alone arm

4 Missing information for 16 patients in Thal + Dex arm and 11 patients in Dex alone arm

Stage (Durie-Salmon), N (%) 1
      I 14 (13.6%) 17 (16.3%)
      II 47 (45.6%) 44 (42.3%)
      III 41 (39.8%) 43 (41.3%)
Immunoglobulin Type, N (%) 2
      IgA 21 (20.4%) 22 (21.2%)
      IgG 63 (61.2%) 60 (57.7%)
      IgM 0 (0.0%) 1 (1.0%)
      Biclonal 0 (0.0%) 1 (1.0%)
Lytic Lesions3
      None 28 (27.1%) 14 (13.5%)
      1-3 lesions 24 (23.3%) 19 (18.3%)
      >3 lesions 34 (33.0%) 41 (39.4%)
Serum Light Chain4
      Kappa 59 (57.3%) 53 (51.0%)
      Lambda 28 (27.2%) 40 (38.5%)
Table 8: Baseline Disease Characteristics (Study 2)

Disease Characteristic
THALOMID/ Dexamethasone
(N=235)
Placebo/
Dexamethasone
(N=235)

KEY: ECOG=Eastern Cooperative Oncology Group

Baseline MM Stage (Durie-Salmon), n (%)
      I 2 (1) 2 (1)
      II 76 (32) 88 (37)
      III 157 (69) 145 (62)
ECOG Performance Status, n (%)
      0 40 (17) 54 (23)
      1 124 (53) 112 (48)
      2 70 (30) 68 (29)
      3 0 (0) 1 (<1)
      Missing 1 (<1) 0 (0)
Lytic Bone Lesions, n (%)
      Present 185 (79) 188 (80)
      Absent 49 (21) 46 (20)
      Missing 1 (<1) 1 (<1)
Bone Marrow Apirate/Biopsy Cellularity, n (%)
      Normal 102 (43) 108 (46)
      Hyperplasia 77 (33) 76 (32)
      Hypoplasia 53 (23) 50 (21)
      Missing 3 (1) 1 (<1)
Baseline β-2 Microglobulin, n (%)
      ≤ 2.5 mg/L 33 (14) 35 (15)
       > 2.5 mg/L 200 (85) 199 (85)
       Missing 2 (1) 1 (<1)

In Study 1, response rate was the primary endpoint. Response rates based on serum or urine paraprotein measurements were significantly higher in the combination arm (52% vs. 36%). The primary efficacy endpoint in Study 2 was time to progression (TTP), defined as the time from randomization to the first documentation of disease progression, based on the myeloma response criteria. A preplanned interim analysis for Study 2 demonstrated that the combination of THALOMID plus dexamethasone was superior to placebo plus dexamethasone with respect to TTP (Table 9).

Table 9: Summary of Efficacy (Study 2)
Thalidomide/Dexamethasone
(N=235)
Placebo/
Dexamethasone
(N=235)

a The 95% confidence intervals about the median overall TTP, or median overall survival. CI: confidence interval; NR: not reached.

b Based on a proportional hazards model comparing the hazard functions associated with treatment groups (thalidomide/dexamethasone:placebo/dexamethasone).

c P-value based on the interim analysis was compared with the nominal significance level of 0.0027. Based on a one-sided unstratified log rank test of survival curve differences between treatment groups.

d Disease response assessments were determined according to the Bladé criteria. Response is the highest assessment of response during the treatment phase of the study.

Time to Progression
       Progressed – n (%) 72 (31) 126 (54)
      Median (Weeks) (95% CIa) 97.7 (61.86, NR) 28.3 (27.71, 36.43)
       Hazard Ratio (95% CI)b 0.43 (0.32, 0.58)
      P-valuec <0.0001
Overall Survival
      Death – n (%) 57 (24) 68 (29)
      Median (Weeks) (95% CIa) NR (112.14, NR) 128.6 (113.43, NR)
      Hazard Ratio (95% CI)b 0.82 (0.57, 1.16)
Myeloma Response Rated – n (%)
      Complete Response (CR) 18 (8) 6 (3)
       Partial Response (PR) 130 (55) 102 (43)
      Overall Response (CR + PR)
      95% CI (%)
148 (63)
(56, 69)
108 (46)
(39, 53)

The Kaplan-Meier plot of the time to progression by treatment group is presented in Figure 1.

Figure 1: Kaplan-Meier Plot of Time to Disease Progression

KEY: Placebo/Dex=placebo/dexamethasone; Thal/Dex=THALOMID/dexamethasone

Erythema Nodosum Leprosum (ENL)

The primary data demonstrating the efficacy of thalidomide in the treatment of the cutaneous manifestations of moderate to severe ENL are derived from the published medical literature and from a retrospective study of 102 patients treated by the U.S. Public Health Service.

Two double-blind, randomized, controlled trials reported the dermatologic response to a 7-day course of 100 mg thalidomide (four times daily) or control. Dosage was lower for patients under 50 kg in weight.

Table 10: Double-Blind, Controlled Clinical Trials of Thalidomide in Patients with ENL: Cutaneous Response
Reference No. of Patients No. Treatment Courses* Percent Responding**

*  In patients with cutaneous lesions

**Iyer: Complete response or lesions absent

**Sheskin: Complete improvement + “striking” improvement (i.e., >50% improvement)

Iyer et al.
Bull World Health
  Organization 1971;45:719
92 204 Thalidomide
75%
Aspirin
25%
Sheskin et al.
Int J Lep 1969;37:135
52 173 Thalidomide
66%
Placebo
10%

Waters reported the results of two studies, both double-blind, randomized, placebo-controlled, crossover trials in a total of 10 hospitalized, steroid-dependent patients with chronic ENL treated with 100 mg thalidomide or placebo (three times daily). All patients also received dapsone. The primary endpoint was reduction in weekly steroid dosage.

Table 11: Double-Blind, Controlled Trial of Thalidomide in Patients with ENL: Reduction in Steroid Dosage
Reference Duration of Treatment No. of Patients Number Responding
Thalidomide Placebo
Waters 4 weeks 9 4/5 0/4
Lep Rev 1971;42:26 6 weeks
(crossover)
8 8/8 1/8

Data on the efficacy of thalidomide in prevention of ENL relapse were derived from a retrospective evaluation of 102 patients treated under the auspices of the U.S. Public Health Service. A subset of patients with ENL controlled on thalidomide demonstrated repeated relapse upon drug withdrawal and remission with reinstitution of therapy.

Twenty U.S. patients between the ages of 11 and 17 years were treated with thalidomide, generally at 100 mg daily. Response rates and safety profiles were similar to that observed in the adult population.

Thirty-two other published studies containing over 1600 patients consistently report generally successful treatment of the cutaneous manifestations of moderate to severe ENL with thalidomide.

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